NaphthyridinesâAn On-Water Approach - American Chemical Society

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Pseudo Five-component Domino Strategy for the Combinatorial Library Synthesis of [1,6] Naphthyridines - An On Water Approach Paramita Das, Tandrima Chaudhuri, and Chhanda Mukhopadhyay ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/co400162m • Publication Date (Web): 14 Oct 2014 Downloaded from http://pubs.acs.org on October 17, 2014

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ACS Combinatorial Science

Pseudo Five-component Domino Strategy for the Combinatorial Library Synthesis of [1,6] Naphthyridines - An On Water Approach Paramita Das,a Tandrima Chaudhurib and Chhanda Mukhopadhyaya,* a

Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata-700009, India

b

Department of Chemistry, Dr. Bhupendranath Dutta Smriti Mahavidyalaya, Hatgobindapur,

Burdwan 713407, India Keywords: on water, 1,6-naphthyridines, hydrophobic aggregation, selectivity

Abstract: This work features the base-promoted on water synthesis of [1,6]-naphthyridines from methyl ketones, malononitrile and phenols or thiols. The reaction conditions were carefully tuned to drive the product selectivity from 3H-pyrroles to [1,6]-naphthyridines. The advantages of this method lie in its simplicity, cost effectiveness, and environmental friendliness, representing a new effort towards the on water synthesis of [1,6]-naphthyridines without starting from a nitrogen-containing heterocycle and highlighting the versatility of the nitrile functional group.

INTRODUCTION

Multicomponent reactions (MCRs)1a,b provide effective tools for combinatorial synthetic chemistry because highly diverse compound libraries can be prepared via convenient one-pot procedures. Attention is often focused on natural product scaffolds and drug-like molecules,1c

1 ACS Paragon Plus Environment


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with particular emphasis on heterocyclic compounds.1d,e As a consequence, multicomponent reactions and related domino reactions have received much recent attention.1f Water is known to enhance the rates and to affect the selectivity of a wide variety of organic reactions.2 Even when rate accelerations are modest, water provides advantages of large heat capacity, making exothermic processes safer and more selective, and easily isolation of organic compounds. Functionalized [1,6]-naphthyridines and their benzo/hetero-fused analogues have attracted much attention from synthetic and medicinal view points.3 Naphthyridine derivatives are widely used for various pharmacological purposes (Figure 1) such as antiproliferative activity,4 HIV-1 integrase inhibition,5 allosteric inhibition of Akt1 and Akt2,6 and selective antagonism of 5-HT4 receptors.7 The majority of the synthetic strategies toward these units8 have relied on condensation of 2amino pyridine derivatives with carbonyl compounds containing an active methylene group or with β-keto esters.9 Transition metal mediated cyclotrimerisation of dialkynyl nitriles has also been recognized as a general method toward [1,6]-naphthyridines10 in addition to the common approach of Lewis acid catalysis of intramolecular hetero Diels-Alder reactions of aldimines.11 Many of these methods suffer from the use of multistep sequences, expensive catalysts,12 hazardous organic solvents, inert atmosphere, lengthy reaction time, and laborious workup.13 Moreover, there are only a few reports of the simple and convenient synthesis of this moiety from readily available and inexpensive starting materials.14,15


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N

N O

N H

N

N

R OR' OR''

R Aaptamine (R = H, R' = Me, R'' = Me) Isoaaptamine (R = Me, R' = H, R'' = Me) HCMV-inhivitors Demethylaaptamine (R = H, R' = H, R'' = Me) 8,9-demethylaaptamine (R = H, R' = H, R'' = H) (R = OMe)

1,6-Naphthyridine:

Marine Natural Products

N N N O

OH

labuanine A: Neuronal Differentiation inducers

Figure 1. Examples of biologically active 1,6-naphthyridines. RESULTS AND DISCUSSION We explored the use of phenols and thiols as synthon for an unprecedented coupling with methyl ketones and malononitrile to create highly substituted [1,6]-naphthyridines (Scheme 1). In previous work,15 we have used ketones, malononitrile and aliphatic amines for the synthesis of [1,6]-naphthyridines. While no base other than the reactant amine was required, the method reported here needs an additional base catalyst. Scheme 2 shows the use of triethylamine as catalysis for a one-pot, pseudo-five-component synthesis of 1,2-dihydro[1,6]-naphthyridines from ketones, malononitrile and phenols in the ecofriendly solvent water. The products were well characterized by 1H NMR,

13

C NMR, 2D NMR, FTIR, elemental analysis, melting point

determination, and X-ray crystallographic analysis.



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Scheme 1. Previous15 and present approaches to substituted [1,6]-napthylpyridines. Our previous work R

H

O NC

CH3

H

H2O (2 mL), 3 h

N R

CN

H3C R

reflux

R = aryl, alkyl 2 mmol 2 mmol

NH2

1 mmol

N N H

CN

N

R

NH2

Our present work O R

NC

CH3

CN

R = aryl, alkyl 2 mmol

2 mmol

OH

Et3N (0.2 mmol)

R5

H2O (2 mL), 4 h H3C R reflux

H

1 mmol

N N H

O

R5

CN

R5 = H, alkyl, aryl

O R

Et3N (0.2 mmol) CH3 NC

CN

R = aryl, alkyl 2 mmol 2 mmol

H2O (2 mL), 4 h reflux

R H H R N H3 C H

C

R

N C

C N

1 h, reflux N

H

NH2 N

H 3C R

SH R6 1 mmol

N S 6 R H CN R6 = H, alkyl, aryl

Scheme 2. Pseudo-five component synthesis of [1,6]-naphthyridines

R

R

XH

O

Et3N (0.2 mmol) CH3

NC

CN

1

2

2 mmol

2 mmol

H

H2O (2 mL), 4 h H3C R reflux

R1 3 (X=O) 1 mmol

NH2 N

N H

X CN 4 (X=O) 30 Examples

R1

Optimization of Reaction Conditions To optimize the reaction conditions, a series of experiments were conducted with a representative reaction of 4-chloro acetophenone (1{1}) (2 mmol), malononitrile (2{1}) (2 mmol) and 4-tert-butyl-phenol (3{10}) (1 mmol) with variation of reaction parameters. The results,


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summarized in Table 1, showed that the nature of the catalyst and the reaction temperature had a significant effect on the yield of the desired [1,6]-naphthyridines (4{1,1,10}) and 7-hydroxy[1,6]-naphthyridines (5{1,1}). Sodium hydroxide was ineffective, at both low and high temperatures (Table 1, entries 1 and 2). In the latter case (100 °C), an unexpected compound 5{1,1} was isolated in 10% yield, presumably by nucleophilic attack of hydroxide in competition with phenoxide. Therefore, the use of a higher concentration of NaOH as base catalyst gave significant improvements in the yield of the 7-hydroxy compound 5{1,1}, isolated in greater proportions relative to naphthyridine (4{1,1,10}) as the temperature was lowered (Table 1, entries 3-5). No product was observed when a background reaction was carried out with no catalyst (entry 6).



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Table 1. Optimization of Reaction Conditions for the Multicomponent Coupling Reactionsa Cl

O

CH3

NH2

OH H

conditions NC

CN

H3C

catalyst Cl 1{1} 2 mmol

2{1} 2 mmol

Cl

Cl

3{10} 1 mmol

amount

NH2 H

N N H

H3C

O CN Cl

4{1,1,10}

temp (°C) time (h)

N N H

OH CN

5{1,1}

yield (%)b

entry

catalyst

(mmol)

solvent

4{1,1,10} 5{1,1}

1

NaOH

0.2

H2O

35

12

0

0

2

NaOH

0.2

H2O

100

3

15

10

3

NaOH

1.0

H2O

100

3

20

40

4

NaOH

1.0

H2O

80

3.5

25

55

5

NaOH

1.0

H2O

70

4

15

65

6

-

-

H2O

100

24

-

-

7

K2CO3

1.0

H2O

100

4

30

40

8

guanidine

0.2

H2O

100

4

84

0

9

DBU

0.2

H2O

100

4

86

0

10

Et3N

0.2

H2O

100

4

94

0

11

Et3N

0.2

H2O

60

8

49

0

12

pyridine

0.2

H2O

100

4

91

0

13

Et3N

0.2

DMSO

120-130

8

74

0

14

Et3N

0.2

DMF

120-130

8

79

0

15

Et3N

0.2

Toluene

100-110

8

81

0

16

Et3N

0.2

ACN

70-80

10

52

0

17

Et3N

0.2

EtOH

70-80

10

51

0

18

Et3N

0.2

MeOH

50-60

12

41

0


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19

Et3N

0.2

DCM

30-35

12

10

0

a

Reaction conditions: 4-chloro acetophenone (2 mmol), malononitrile (2 mmol), 4-tert-butylphenol (1 mmol), different solvents (2 mL), different catalysts, different temperatures, different times. bIsolated yields. To prevent the intrusion of the 7-hydroxycompound (5{1,1}) and to acquire the desired [1,6]-naphthyridine (4{1,1,10}) under environmentally benevolent conditions, we tested a panel of organic bases. Guanidine and DBU provided only the desired [1,6]-naphthyridine (4{1,1,10}), but yields were found to be slightly better with pyridine and Et3N at 100 °C (Table 1, entries 812). Here, the weaker bases may induce less polymerization of the ketone as a competitive side reaction, leading to higher yields. Triethylamine was chosen as the catalyst for further tests of solvent effects. Interestingly, isolated yields were found to be comparatively low in common high boiling organic solvents such as DMSO, DMF, and toluene (entries 13-15), due mainly to difficulties in isolation. Also prolonged times were required for reaction completion in these mixtures. Lower-boiling solvents (acetonitrile, EtOH, MeOH, DCM) did not allow the required high temperatures with standard glassware, and afforded poor yields of 4{1,1,10} (Table 1, entries 16-19). Thus, the best yield, cleanest reaction, and most facile workup were achieved in water as a solvent employing 0.2 mmol Et3N (Table 1, entries 10). Substrate scope Various methyl ketones, phenols, and malononitrile were tested with the optimized reaction conditions, giving 30 variants using this protocol (Figure 2, Table 2). Both aliphatic alcohols and phenols afforded excellent yields, the latter tolerating both electron-withdrawing and electrondonating substituents on the aromatic ring. Acid-sensitive (containing hydroxy groups) and sterically bulky alcohol phenols (β-naphthol, α-naphthol) also reacted very efficiently with no



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side products. Therefore, the present protocol has general applicability, accommodating a variety of substitution patterns. Good diversity in the ketone component was also tolerated. Especially noteworthy was the successful

use

of

electron-rich

ketones

[4'-methoxyacetophenone

and

3',4'-

dimethoxyacetophenone], considering the difficulty usually associated with Knoevenagel condensation reactions of these substrates (Table 2, 4{4,1,2}-4{5,1,10}). Sterically bulky 2acetylfluorene was readily converted into the desired product (4{6,1,10}), and aliphatic ketones were also examined (4{7,1,1}). To further expand the scope of the reaction the use of heteroaryl methyl ketones was investigated (4{2,1,1}-4{2,1,10}). Steric considerations seem to have limited the process in one case (4{7,1,1}), in which the methyl ketone, but no other ketone, gave good yield, perhaps because of crowding in intermediate 10 (Scheme 3). A representative structure was confirmed by X-ray crystallographic analysis of compound (4{1,1,11}) (CCDC 926217) (Table 2).


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R

O R

NC

CH3

2{1} 2 mmol

1{1-7} 2 mmol

1{2} H3CO

1{4}

R5

4{1{1-7},2{1},3{1-11}} OH

OH

OH

CH3 O

CH3

O CN

OH

1{3}

O

CH3

Cl

3{1}

3{2}

3{3}

OH

3{4} OH

OH

OH

CH3

1{5}

H3CO

OH O 1{6}

N H

O CH3

1{1}

H3CO

N

OH

S

CH3

H2O (2 mL), 4 h H3C R reflux, 100 0C

3{1-11} 1 mmol

O

O

Cl

OH R5

CN

NH2

H

Et3N (0.2 mmol)

O CH3

CH3

3{5}

3{7}

3{6} OH

OH

3{8}

CH3

OH

OH

OH

CH2OH

1{7}

Chemset 1 3{9} NC

CH3

3{11}

CN

2{1} Chemset 2

3{10}

O2N

3{13}

3{12} Chemset 3

Figure 2. Components used for the synthesis of [1,6]-naphthyridines.



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Table 2. Synthesized [1,6]-naphthyridines naphthyridines and ORTEP representation of 4{1,1,11} (CCDC 926217). Structure

Cl

NH2

H CH3

N N O H CN

R5

Cl

S NH2 H CH3

N

N O S H CN

R5

NH2

H

N

H3C

5

N H

O

R

R5OH

Product

3{1} 3{2} 3{3} 3{4} 3{5} 3{6} 3{7} 3{8} 3{9} 3{10} 3{11} 3{12} 3{13}

44{1,1,1} 4 4{1,1,2} 4 4{1,1,3} 4 4{1,1,4} 4 4{1,1,5} 4 4{1,1,6} 4 4{1,1,7} 4 4{1,1,8} 4 4{1,1,9} 4{1,1,10} {1,1,10} 4{1,1,11} {1,1,11} 4{1,1,12} {1,1,12} 4{1,1,13} {1,1,13}

Yield (%) 94 89 91 91 89 90 93 92 92 94 93 92 88

3{1} 3{2} 3{3} 3{4} 3{7} 3{8} 3{9} 3{10}

44{2,1,1} 4 4{2,1,2} 4 4{2,1,3} 4 4{2,1,4} 4 4{2,1,7} 4 4{2,1,8} 4 4{2,1,9} 4{2,1,10} {2,1,10}

92 91 91 92 93 93 90 93

3{1} 3{10}

44{3,1,1} 4{3,1,10} {3,1,10}

93 94

CN

4{1,1,11} (CCDC CCDC 926217)

Structure

R5OH

Product

Yield (%)

3{1} 3{10}}

4{5,1,1} 4{5,1,10}

92 93

3{10}}

4{6,1,10}

93

OMe OMe NH2

H H3C

MeO

N 5

N H

O

R

CN

OMe

NH2

H H3C

N N H

O

R5

CN

OCH3 NH2

H H3 C

N N H

O

R5

3{2} 3{10} 3{11}

4 4{4,1,2} 4{4,1,10} {4,1,10} 4{4,1,11} {4,1,11}

91 94 93

CN

H3CO


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A plausible mechanism for the multicomponent condensation process is shown in Scheme 3. Initial Knoevenagel condensation of the carbonyl compound with malononitrile in the presence of a base15,16 was supported by NMR observation of the resulting product [(7), (R = 4'-Cl-C6H4-)] isolated after 30 min. This intermediate (7) is proposed to undergo Michael-type reaction with another molecule of 7, with subsequent malonitrile elimination to form intermediate 10. Another attack of malononitrile triggers ring closure to yield intermediate 11, which tautomerises to give 12. Though we could not isolate the intermediate 10, structures 12{1,1} and 12{2,1} were characterized by X-ray analysis (Figure 3a,b). Finally the second ring is produced by attack of phenols on the electrophilic nitrile group in intermediate 12, driven by aromatization in the target compound.



Scheme 3. A plausible mechanism for the formation of [1,6]-naphthyridines.

NC

-H+/+H+

NC

NC

R

H NC

Et N Et Et H R OH NC C N N .. +/+H+ C CN -H NC CH3 R CH2 H NC H H2C R -H2O 7 8 N 6 Et Et Et NC CN

O

Et Et N ..

Et

CH3

1 +H+

..

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2

-H+/+H+ R 7 CH3 Et

Et Et N

R H

H

R

C C CH3 N 10

R

N

-H+/+H+ CN

CN CN

H

..

C C CH3 N

R

H

N Et Et Et

N

-H+/+H+ NC

NC

CN R

CN

R CN CN H CH CH 3 H

9

CN R' XH

R H H R N H3C 11

C

H

R

N C C

-H+/+H+ N N

H H R N H3C H 12

C

3 Et3N

N C

H H H3C R

N X

C N

R

NH N

N H

R'

X CN

-H+/+H+ R H H3C R

R'

NH2 N

N H 4

X CN R'


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(b)

(a)

12a 12{1,1}

12b 12{2,1}

Figure 3. (a) ORTEP representation of intermediate 12{1,1} (CCDC 926218). (b) 12{2,1} (CCDC 926219). Thus the present reaction comprises a relay processes of the following domino sequences: (1) two-component Knoevenagel reaction, (2) two-component Michael-type reaction followed by elimination, (3) two-component ring closure, and (4) two-component cyclization aromatization process (Scheme 3). This pathway was examined by DFT calculations,17 in which the proposed transition structures were identified (see Supporting Information, Fig S1-S6). All the optimized geometries of reactants, products and corresponding TS are shown in energy profile diagrams in Supporting Information (Fig S7), which identify reasonable “downhill” energetics for the intermediates. Rationale of rate acceleration in water Even though Knoevenagel condensations accomplish a net dehydration event, the reaction described here is favored in an aqueous medium. Both a standard hydrophobic effect (i.e., the propensity of hydrophobic molecules to associate in order to minimize their contact surface with water, leading to effective concentration of the reactants18) and an “on-water” effect (in which



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OH groups at oil-water phase boundary can then play an important role in catalyzing reactions via the formation of hydrogen bonds) can be proposed. Table 1 shows much faster and higher yielding reactions using the same catalyst and reactants in water (entry 10) than in organic other solvents (entries 13-19). Since the aqueous reaction mixture remains heterogeneous throughout the course of reaction, this qualifies as an on water synthesis. The replacement of phenols with thiols gave the anticipated thiol-substituted [1,6] naphthyridines (Figure 4, Table 3). Both aromatic and aliphatic thiols afforded excellent yields, including those with electron-withdrawing as well as electron-donating groups. Sterically bulky naphthalene-2-thiol also reacted very efficiently (19{1,1,6}, 19{2,1,6}and 19{3,1,6}). We have confirmed the structure of compound (19{4,1,1}) unambiguously by X-ray crystallographic analysis (CCDC 956062) (Table 3). O R

Et3N (0.2 mmol) CH3 NC

1{1-7} 2 mmol

CN

H2O (2 mL), 4 h reflux

2{1} 2 mmol

R H H R N H3C H

C

R

N C

C N 12{1{1-7},2{1}}

1 h, reflux N SH R6 14{1-8} 1 mmol

NH2

H H3C R

N N H

S CN

R6

19{1{1-7},2{1},14{1-11}} 25 Examples

SH 14{1} SH

SH Cl

Cl

SH

14{2}

14{3}

SH

SH

14{6}

14{7}

SH 14{4}

H3C

SH 14{5}

14{8}

Chemset 14

Figure 4. Components used for the synthesis of thiol-substituted naphthyridines.


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Table 3. Naphthyridines synthesized with thiol nucleophiles; ORTEP representation of 19{4,1,1} (CCDC 956062). Structure Cl

NH2

H CH3

N N S H CN

R6

R6SH

Product

14{2} 14{3} 14{5} 14{6} 14{7}

19{1,1,2} 19 19 19{1,1,3} 19 19{1,1,5} 19 19{1,1,6} 19 19{1,1,7}

Yield (%) 93 93 95 90 91

14{1} 14{2} 14{3} 14{4} 14{5} 14{6} 14{7}

19{2,1,1} 19 19 19{2,1,2} 19 19{2,1,3} 19 19{2,1,4} 19 19{2,1,5} 19 19{2,1,6} 19 19{2,1,7}

93 93 92 93 91 91 90

14{3} 14{5} 14{6} 14{7} 14{8}

19{3,1,3} 19 19 19{3,1,5} 19 19{3,1,6} 19 19{3,1,7} 19 19{3,1,8}

93 92 90 92 90

14{1} 14{2} 14{4}

19{4,1,1} 19 19 19{4,1,2} 19 19{4,1,4}

91 90 91

Cl

Structure OMe OMe

H 3C

MeO

S NH2 H CH

N

3

N S S H CN

R6

NH2

H

N

H3C

6

N H

S

R

CN

NH2

H

N N H

S

R6SH

Product

14{1}} 14{2}} 14{3}}

19{5,1,1} 19{5,1,2} 19{5,1,3}

Yield (%) 90 91 89

14{1}}

19{6,1,1}

91

14{1}}

19{7,1,1}

87

R6

CN

OMe

NH2

H H3C

N 6

N H

R

NH2

H H3C

S CN

N N H

S

R6

CN

OCH3 NH2

H H3C

N N H

S

R6

CN

H3CO

19{4,1,1} (CCDC CCDC 956062)

Hydroxide was similarly used as a nucleophile to prepare four 7-hydroxy-[1,6]naphthyridines (5). The optimized reaction condition and structures, obtained in moderate yields, are shown in Figure 5.



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R

O R

Page 16 of 24

H2O (2 mL), 4 h CH3

NC

CN

NaOH 70 C

2{1} 2 mmol

N OH H CN 5{1{1-4},2{1}} 4 Examples

1 mmol

Cl

S

NH2 H Cl

H

N

N H3C H

OH

S

CN

NH2 H

N N H

OH CN

5{3,1}, 70%

OH CN

5{2,1}, 70% OCH3

NH2

H3C

NH2 N

N H3C H

5{1,1}, 72%

H

N

H3C R

0

1{1-4} 2 mmol

NH2

H

H3CO

N

N H3C H

OH CN

5{4,1}, 69%

Figure 5. Synthesis of hydroxy-inserted [1,6]-naphthyridines. CONCLUSION We highlight here the synergistic effects of the combined use of multi-component reactions between methyl ketones, malononitrile, and phenols or thiols in water as an environmentally benevolent solvent for the preparation of functionally rich heterocycles. This is an excellent example of a true on water synthesis since the rate enhancement in water in comparison to organic solvents is vividly discernible and thus it adds a new entry to the list of on water transformations. By controlling the addition time of thiol nucleophiles, we were able selective prepare either 3H-pyrroles or[1,6]-naphthyridines. This protocol not only represents a promising green route to an interesting new class of compounds, involving the creation of three C-C, two C-N, and one C-S or C-O bond in a single operation. Two nitrogen-containing rings are


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made without starting from any nitrogen-containing heterocyclic moiety, and the presence of a cyano group in the naphthyridines makes them useful synthetic intermediates for the preparation of other nitrogen-containing heterocycles.19 ASSOCIATED CONTENT Supporting Information. Supporting Information Detailed computational studies, Molecular coordinate of optimized geometries, IRC plots of the Transition states, experimental procedure, spectral data, copies of 1

H and 13C NMR spectra of all the new compounds are provided. This material is available free

of charge via the Internet at http://pubs.acs.org/. AUTHOR INFORMATION Corresponding Author E-mail: [email protected] Author Contributions All authors contributed equally. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT One of the authors (PD) thanks the Council of Scientific and Industrial Research, New Delhi for her fellowship (SRF), the CAS Instrumentation Facility, Department of Chemistry, University of Calcutta for spectral data. REFERENCES



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Pseudo Five-component Domino Strategy for the Combinatorial Library Synthesis of [1,6] Naphthyridines - An On Water Approach GRAPHICAL ABSTRACT R

NH2

H

N

H3C R

N H

S CN

25 New compounds SH

R4

1 h, reflux

R4 R H H R N H3C H

C

N C

N

C N

Et3N (0.2 mmol) H2O (2 mL), 4 h reflux H O (2 mL), 4 h Et3N (0.2 mmol) H2O (2 mL), 4 h reflux R H H3C R

H2O (2 mL) 4 h, 70 0C OH

NH2

NaOH

R H

N N H

O

H3C R

R1 R1

CN

30 New compounds

NH2 N

N H

OH CN

4 New compounds



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Page 24 of 24

Pseudo Five-component Domino Strategy for the Combinatorial Library Synthesis of [1,6] Naphthyridines-An On Water Approach Paramita Das, Tandrima Chaudhuri and Chhanda Mukhopadhyay* R

NH2

H

N

H3C R

N H

S CN

25 New compounds SH

R4

1 h, reflux

R4

R H H R N H3C H

C

N C

N

C N

Et3N (0.2 mmol) H2O (2 mL), 4 h reflux Et3N (0.2 mmol) H2O (2 mL), 4 h reflux R H H3C R

H2O (2 mL) 4 h, 70 0C OH

NH2

NaOH

R H

N N H

O

H3C R

R1 R1

CN

30 New compounds

NH2 N

N H

OH CN

4 New compounds

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